ABSTRACT Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by heterogeneity of presentation, an undulating course, and a remarkably elevated risk for premature cardiovascular disease. Platelets have been understudied as a relevant contributor to premature atherosclerosis in SLE. Yet these cells, which contain transcripts and the necessary molecular machinery to conduct translation, are intercellular regulators of inflammation and immune activation and play a key role in atherothrombosis. Platelets express low affinity type 2 receptor (Fc?RIIA) whose ligand is the Fc portion of IgG. A single amino acid substitution, H131R, in the extracellular ligand binding domain increases the affinity for IgG and may account for individual variation in platelet activation, specifically gain of function. Leveraging a well-characterized SLE cohort, we identified a significant enrichment of carotid plaque in patients carrying at least one copy of the variant compared to those homozygotic for the ancestral gene. In a second SLE cohort, a significant increase in monocyte-platelet aggregates (MPA) in patients carrying the variant versus ancestral gene was observed. Although not yet assessed for genotype, SLE platelets exhibited a hyperreactive phenotype relative to healthy donors. Accordingly, it is hypothesized that platelet activity measurements and platelet-derived coding and non-coding RNA are significantly influenced by Fc?RIIA genotype. Two aims provide complementary studies to evaluate the underlying mechanism of increased platelet activity in SLE. In Specific Aim 1 the relationship between SLE platelet phenotype and transcriptome in the context of Fc?RIIA genotype will be investigated. To test the influence of Fc?RIIA genotype on platelets, a multidimensional panel of platelet activity markers representing different pathophysiological mechanisms will be measured, including: light transmission aggregometry (LTA); leukocyte- and monocyte-platelet aggregates; reticulated platelets; platelet receptor expression of PAC-1, CD40 ligand, P-selectin; platelet size; and the platelet transcriptome. Readouts will be assessed and compared in three groups of SLE subjects: H/H homozygotes, R/H heterozygotes, and R/R homozygotes. In Specific Aim 2 the goal is to molecularly assess platelet reactivity dependent on Fc?RIIA ligation and the impact of genotype on the phenotype of the vascular targets, endothelial cells (ECs) and macrophages. In contrast to Specific Aim 1, the approach utilizes platelets from healthy controls (H/H, R/H, and RR) since platelets from SLE patients may be intrinsically coated with immune complexes (ICs) accounting for baseline reactivity. Co-treatment of platelets with anti-CD9 will serve as a proxy of ICs and Fc?RIIA dependency approached using blocking antibodies. ECs and macrophages co-cultured with anti-CD9 platelets will be assessed for both pro-inflammatory and protective signaling cascades. Identification of a novel biomarker to gauge response to therapy, and/or to be used to identify patients at increased risk for premature cardiovascular disease and likely to benefit from anti-platelet agents, would be an advance.